The long term objective of this proposed research study is to develop a safe and effective treatment for ovarian cancer, which has an estimated prevalence of 167,000 patients in the United States. In more than 55% of patients, ovarian cancer recurs within two years after treatment with first-line chemotherapy. Second and third line therapies are generally ineffective and toxic. This proposal describes a novel approach to ovarian cancer treatment that involves stimulation of patients'immune systems against cancer. An interleukin-12 (IL-12) gene plasmid, formulated with a biocompatible polymer delivery system, is administered intra-peritoneally to increase IL-12 concentrations locally for several days or longer after each injection. IL-12 is a potent anticancer cytokine that works by activating the patient's immune system and inhibiting tumor blood supply. The clinical proof of concept of the intended use of intra-peritoneal IL-12 therapy (also called EGEN-001) has been demonstrated in two Phase 1 clinical trials. Repeated administration of intra-peritoneal EGEN-001, alone or in combination with chemotherapeutic agents, in recurrent ovarian cancer patients showed evidence of safety, adequate biological activity, and encouraging efficacy, leading to a recommendation by the clinical advisory board for further studies for determination of the optimal dose and dosing frequency for future development. The specific aim of this proposed Phase 2 trial is to determine the efficacy and safety of long treatment cycles of EGEN-001 intra-peritoneally in platinum-resistant recurrent ovarian cancer patients. Primary end points include progression-free survival for at least six months, objective tumor response, and frequency and severity of adverse effects. The ability to treat persistent ovarian cancer patients chronically with a safe and effective immunotherapeutic drug offers a new treatment paradigm for this chronic disease that currently has limited effective treatment options. The proposed study will be conducted at nationally recognized clinical centers of the Gynecological Oncology Group, a cooperative group of the National Cancer Institute.